Anaplastic Multiple Myeloma With a Novel Proliferation of Pleomorphic Binuclear Plasma Cells

This study describes an unusual case of multiple myeloma that progressed to anaplastic multiple myeloma in the pleural fluid. The Wright-stained cytospin of the pleural fluid showed a predominant population of mononuclear plasma cells with pleomorphic nuclei, characterized by both small and large nuclei, which is typical of anaplastic multiple myeloma. However, there were also more binuclear plasma cells with pleomorphic nuclei. Morphometric analysis showed that the mean nuclear length was 1.9-fold and 2.3-fold higher in the large nuclei compared to the small nuclei for the mononuclear plasma cells and binuclear plasma cells, respectively (p<0.001). The patient received B cell maturation antigen chimeric antigen receptor T cell (CAR-T) therapy for relapsed disease, with a significant reduction of the serum monoclonal paraprotein level at day 51 post-therapy. Pathologists should be aware that pleomorphic binuclear plasma cells can be part of the morphologic spectrum in anaplastic multiple myeloma.


Introduction
Multiple myeloma is a neoplastic proliferation of plasma cells that usually originates in the bone marrow [1].Extramedullary involvement is a feature of advanced disease and can rarely involve the pleural fluid [2].Neoplastic plasma cells can vary in their morphology, ranging from mature forms indistinguishable from normal plasma cells to plasmablastic, lymphoplasmacytic, pleomorphic, and other morphologic subtypes [1].Anaplastic multiple myeloma is a rare morphologic variant characterized by pleomorphic plasma cells with large nuclei, as first reported in 1983 by Foucar et al. [3].
We report a rare case of multiple myeloma that transformed into anaplastic multiple myeloma in the pleural fluid.Our case was unique in that the Wright-stained cytospin of the pleural fluid showed pleomorphic binuclear plasma cells.This study describes the clinical, pathologic, and morphometric features of this unusual manifestation of anaplastic multiple myeloma.

Case Presentation
A 73-year-old female presented with a chief complaint of dyspnea and fatigue for two days.Past medical history was significant for IgG kappa multiple myeloma, diagnosed seven years earlier as a stage one disease.Previous myeloma therapy included induction with RVD (lenalidomide, bortezomib, dexamethasone) at diagnosis followed by lenalidomide maintenance, RVD for first bone marrow relapse, DPD (daratumumab, pomalidomide, dexamethasone) for second bone marrow relapse, KPD (carfilzomib, pomalidomide, dexamethasone) for third bone marrow relapse, and KCD (carfilzomib, cyclophosphamide, dexamethasone) for fourth bone marrow relapse and bridging therapy prior to planned chimeric antigen receptor T cell (CAR-T) therapy.The patient declined autologous hematopoietic stem cell transplantation early after diagnosis.A routine bone marrow biopsy was performed 60 days prior to the current presentation, and the morphology, flow cytometry, conventional cytogenetics, and fluorescence in situ hybridization results are shown in Table 1.

TABLE 2: Pertinent laboratory results
The Wright-stained cytospin of the pleural fluid showed 98% atypical plasma cells with pleomorphic morphology.There were five distinct plasma cell subtypes based on the number of nuclei per cell and the size of the nuclei.These subtypes included mononuclear plasma cells with small nuclei, mononuclear plasma cells with large nuclei, binuclear plasma cells with small nuclei, binuclear plasma cells with large nuclei, and multinucleated plasma cells (three to five nuclei per cell) with small nuclei.A low-power view of the atypical plasma cells in the pleural fluid is shown in Figure 1.

FIGURE 1: Pleural fluid cytospin showing atypical plasma cells (Wright stain, 200x)
Mononuclear plasma cell with small nucleus (red arrowhead), mononuclear plasma cell with large nucleus (black arrowhead), binuclear plasma cell with small nuclei (red arrow), and binuclear plasma cell with large nuclei (black arrow) A typical example of a mononuclear plasma cell with a large nucleus is shown in Figure 2. 2024   Mononuclear plasma cell with large nucleus (arrow) and mononuclear plasma cell with small nucleus (arrowhead) A typical example of a mononuclear plasma cell with a large nucleus and abundant giant cytoplasmic vacuoles is shown in Figure 3.  Binuclear plasma cell with large nuclei (black arrow), binuclear plasma cell with small nuclei (black arrowhead), and mononuclear plasma cell with small nucleus (red arrowhead) A typical example of a multinucleated plasma cell with small nuclei is shown in Figure 5.  Morphometric analysis of the different plasma cell subtypes was performed on digital microscopic images of the Wright-stained cytospin at 1000x magnification using an Olympus BX41 microscope (Evident Scientific, Inc., Waltham, MA), an Infinity 1 digital camera (Lumenara Corporation, Ottawa, ON, Canada), and Infinity Analyze software release 6.5.3 (Lumenera Corporation).Nuclear length was defined as the length of the nucleus at its maximum dimension.The mean nuclear length was 1.9-fold higher and 2.3-fold higher in the large nuclei compared to the small nuclei in the mononuclear and binuclear plasma cells, respectively.The mean nuclear length of the nuclei within the multinucleated plasma cells was similar to the mean nuclear length of the small nuclei within the mononuclear and binuclear plasma cells.The percentages, nuclear lengths, and morphologic descriptions of the different plasma cell subtypes are shown in Table 3.

TABLE 3: Analysis of plasma cell subtypes in pleural fluid
NA: not applicable 1 Control specimen is a pleural fluid cytospin from a patient with reactive plasmacytosis. 2 Nuclear length is the mean +/-1 standard deviation. 3All pvalues are based on the two-tailed t-test. 4p-value is a comparison with the control small nuclei. 5p-value is a comparison with the case report mononuclear small nuclei. 6p-value is a comparison with the case report binuclear small nuclei.
The patient received a B cell maturation antigen CAR-T cell infusion using ciltacabtagene autoleucel (ciltacel).Therapy was well tolerated, and at day 51 post-therapy, there was an 89% reduction in the serum IgG kappa paraprotein level (from 5.58 g/dL to 0.59 g/dL).

Discussion
To our knowledge, this is the first reported case of anaplastic multiple myeloma with pleomorphic binuclear plasma cells [1].These cells were identified morphologically on the Wright-stained cytospin of the pleural fluid.Morphometric analysis demonstrated two populations of binuclear plasma cells, one with small nuclei and the other with large nuclei having more than double the nuclear length of the small nuclei.There was also a predominant population of mononuclear plasma cells with small nuclei and large nuclei, as well as a minor population of multinucleated plasma cells with small nuclei.
Pleural fluid metastasis is a rare extramedullary manifestation that affects 0.8% of multiple myeloma patients [2].It can occur at presentation or at relapse and is sometimes accompanied by bone marrow involvement.The prognosis is poor, with a median survival of four months after the onset of pleural fluid metastasis [11].Our case is the first report of anaplastic multiple myeloma involving the pleural fluid.
Anaplastic multiple myeloma has a poor prognosis.In 1990, the mean survival was 3.2 months after the onset of anaplastic disease [5].In 2022, the median survival was 1.5 years, compared to 4.9 years for nonanaplastic multiple myeloma [15].We found no previous cases in the literature describing the therapeutic response of this myeloma variant to CAR-T cell therapy.To our knowledge, this is the first report of anaplastic multiple myeloma showing a favorable early response to B cell maturation antigen CAR-T cell therapy.

Conclusions
This case report demonstrated that anaplastic multiple myeloma can show pleomorphic binuclear plasma cell morphology.Morphometric analysis was useful in characterizing the size of individual nuclei within the various plasma cell populations.In addition, anaplastic multiple myeloma can present as a pleural effusion and can show a favorable early response to B cell maturation antigen CAR-T cell therapy.Pathologists should be aware that pleomorphic binuclear plasma cells can be part of the spectrum of morphologic abnormalities in anaplastic multiple myeloma.

FIGURE 2 :
FIGURE 2: Pleural fluid cytospin showing a mononuclear plasma cell with a large nucleus (Wright stain, 1000x)

FIGURE 3 :
FIGURE 3: Pleural fluid cytospin showing a mononuclear plasma cell with a large nucleus and abundant giant cytoplasmic vacuoles (Wright stain, 1000x)

FIGURE 5 :
FIGURE 5: Pleural fluid cytospin showing a multinucleated plasma cell with five small nuclei (Wright stain, 1000x) Multinucleated plasma cell with five small nuclei (black arrow), binuclear plasma cell with small nuclei (black arrowhead), and mononuclear plasma cell with small nucleus (red arrowhead)